Method of inducing analgesia by



United States Patent M 3,125,488 METHOD OF INDUCING ANALGESIA BY 4-(p- CHLOROPHENYL) 1,2,3,6 TETRAHYDRO- PYRIDINE John H. Biel, Milwaukee, Wis, assignor to Lakeside Laboratories, Inc, Milwaukee, Wis., a corporation of Delaware N0 Drawing. Filed Aug. 8, 1961, Ser. No. 129,951

6 Claims. (Cl. 167-65) This invention relates to chemical compounds having medicinal activities. More particularly, this invention 1s concerned with the use of certain pyridine derivatives as medicinals in animals, as well as novel pharmaceutical compositions containing the pyridine compounds.

It has been found according to the present invention that 4-phenyl 1,2,3,6 tetrahydropyridines, and nontox c pharmaceutically acceptable salts thereof, exert analgetlc, spasmolytic and sedative activity in animals. :Ihese compounds have not yet been demonstrated climcally to be effective in humans.

The 4-phenyl 1,2,3,6 tetnahydropyridines which appear to exert such activity are the compounds of the formula either as the free bases, or salts thereof, wherein R is hydrogen, a lower alkyl such as methyl, ethyl, propyl and isopropyl, an analkyl group and particularly a phenyllower alkyl such as benzyl and phenethyl, a lower alkenyl such as allyl, a lower alkynyl such as propargyl, an amino substituted lower alkyl such as dimethylaminoethyl, and R is hydrogen, or at least one substituent such as a halogen such as chlorine and bromine, a halo lower alkyl such as chloromethyl and trifluoromethyl, nitro, a lower alkyl such as methyl and ethyl, a lower alkoxy such as methoxy and ethoxy, a 'carbolower alkoxy group such as carbomethoxy and oarbethoxy, or a lower alkylenedioxy such as 3,4-methylenedioxy.

Many compounds of the described group are reported in the J. Am. Chem. Soc, 72, 3134 '(1950); 77, 5698 (1955), and 78, 1702 (1956).

Some of the specific compounds which can be used are:

4-phenyl-1,2,3,6-tetrahydropyridine,

4-phenyl-N-methyl-1,2,3,6-tetrahydropyridine,

4-phe nyl-N-benzyl-l ,2, 3 ,6-tetr-ahydropyridine,

4-phenyl-N-phenethyl-1,2,3,6-tetrahydropyridine,

4-phenyl-N-(2dimethylaminoethyl) 1,2,3,6 tetrahydropyridine,

4- p-chlorophenyl) 1,2, 3 6-tetr-ahydropyridine,

4- p-trifiuoromethylphenyl) -1, 2, 3 ,6-tetrahydropyridine,

4- (m-carbethoxyphenyl) 1,2,3,6-tetrahydropyridine,

4-(3,4-methylenedioxyphenyl) 1,2,3,6 tetrahydropyridine,

4-(p-chlorophenyl)-N-allyl 1,2,3,6 tetrahyd-ropyridine and 4-(p-methylphenyl) N propargyl 1,2,3,6 tetrahydropyridine.

Such compounds can be employed as the base or as nontoxic phar-maceutically acceptable acid addition salts including the hydro-chloride, sulfate, phosphate, maleate, fumarate and citrate, as well as salts formed with aromatic carboxylic acids containing an ortho phenolic hydroxy group, such as salicylic acid.

Although one or more of the 4-pheny1-1,2,3,6-tetnahydropy-ridines can be administered as the pure compounds to animals, it is advisable, however, to first combine one or more of the compounds with a suitable phar- 3,125,488 Patented Mar. 17, 1964 maceutical carrier to attain a more satisfactory size to dosage relationship.

Pharmaceutical carriers which are liquid or solid can be used. The preferred liquid carrier is water. Flavoring materials may be included in the solutions as desired.

Solid pharmaceutical carriers such as starch, sugar, talc and the like may be used to form powders. The powders may be used as such for direct administration, or, instead, the powders may be added to suitable foods and liquids, including water, to facilitate administration.

The powders also may be used to make tablets, or to fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid may be used to form the tablets.

Unit dosage for-ms such as tablets, capsules and suppositories may contain any suitable predetermined amount of one or more of the compounds as the base, or in the form of a nontoxic salt, and may be administered one or more at a time at spaced intervals. Such unit dosages can contain, illustnatively, from about 5 to 500 mgm, and advisably 15 to rngm, of an active compound. Variation in activity between compounds is to be expected. Such variations are to be taken into account in utilizing these compounds. Such determinations are readily made by those skilled in the art. Daily dosages of about 0.01 to 6.0 are suitable. The oral route of administration is preferred.

Representative of the analgetic acivity of these compounds is that of 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine. Its analget-ic acivity was determined using the tail clamp procedure described in the British Journal of Pharmacology, 9, 280 (1954). This method employs the application of a painful stimulus to the root of an animals tail and uses the time required for the animal to react to the stimulus as a measure of analgetic activity. The analgetic value is the dose required to give a 100 percent increase in reaction time and is measured in mg/ kg. Using this method, 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine HCl was active at 5.3 mg./ kg. (oral, mice) while codeine was active at 14.0 mg./kg. (oral, mice) and Analexin [2-(beta-hydroxyphenethylamino) -pyridine] at 115.0 mg/kg. (oral, mice).

A typical tablet can have the composition:

The salicylate salts of the 4-pheny1-1,2,3,6-tetrahydropyridine compounds are considered novel and are believed, in general, to possess more pronounced analgesia than the b ases or other salts.

The following example illustrates the preparation of the salicylate salts.

EXAMPLE 4-(p-Chl0r0phenyl) -1,2,3,6-Tetrahydropyridine Salicylate A 10 gm. sample (0.044 mole) of 4-(p-chlorophenyl)- 1,2,3,6-tetrahydnopyridine hydrochloride was dissolved in water, made alkaline with potassium carbonate and the solid base collected by filtration and dried in vacuo. The base was dissolved in 300 ml. of warm isopropyl alcohol and filtered into a solution or 6.07 gm. (0.044 mole) of salicylic acid in 50 ml. of ethyl ether. Precipitation occurs immediately. The solids were filtered under anhydrous conditions, Washed well with ether and oven dried, yielding 12.5 gm. (85.7 percent), M.P. 231233 C. '(d).

Analysis.-Calcd. for C -l-I C1NO N, 4.22; N.E. 331.8. Found: N, 4.40; N.E. 314.16.

A 2 gram sample was recrystallized from a hot mixture e of 100 ml. of acetonitr-ile and 15 ml. of ethanol, M.P. 23l-233 C.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

What is claimed is:

1. A therapeutic composition in dosage unit form comprising a pharmaceutical carrier and from 5 to 500 .rngm. of 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine.

2. A therapeutic composition in dosage unit form comprising a pharmaceutical carrier and from 5 to 500 mgm. of 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine salicylate.

3. A therapeutic composition in dosage unit form comprising a pharmaceutical carrier and from 5 to 500 mgm. of 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride.

4. The method of inducing analgesia in an animal which comprises administering to the animal a safe but References Cited in the file of this patent UNITED STATES PATENTS 2,855,342 Wagner et a l. Oct. 7, 1958 2,895,877 Marsh July 21, 1959 2,929,818 Janssen Mar. 22, 1960 2,967,182 Pohland Jan. 3, 1961 OTHER REFERENCES Foster: Chem. Abst., volume 42, pages 983-984, 1948. Buchi: Chem. Abst., volume 48, 1954, page 13083(i). 

1. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FROM COMPRISING A PHARMACEUTICAL CARRIER AND FROM 5 TO 500 MAGM. OF 4-(P-CHLOROPHENYL)-1,2,3,6-TETRAHYDROPYRIDINE. 